背景：传统化疗的主要挑战在于缺乏选择性和特异性，导致明显的副作用。使用小分子药物偶联物 (SMDC) 可通过将细胞毒性药物与靶向载体偶联来确保将其特异性递送至肿瘤部位。通过选择与生长抑素受体亚型 2 (SSTR2) 特异性结合的靶向载体，这一有前途的策略可以应用于神经内分泌肿瘤 (NET)。此外，将双功能螯合物掺入分子中可以实现诊断性和治疗性放射性核素的络合。因此，它有助于监测 SMDC 在体内的分布，并允许实施联合治疗。在我们的研究中，我们设计了 eSOMA-DM1，这是一种通过螯合桥接头 (N3-Py-DOTAGA) 将 SSTR2 靶向奥曲酸肽和细胞毒剂 DM1 结合在一起的 SMDC。这种方法保证靶向载体和药物在相反位点缀合，以避免不期望的空间位阻效应。方法：DM1 部分 (4) 的合成涉及三步合成路线，然后与环肽 N3-Py-DOTAGA-d-Phe-cyclo[Cys-Tyr-d-Trp-Lys-Thr] 缀合-Cys]-Thr-OH，通过无铜点击反应，产生 eSOMA-DM1。随后用[111In]InCl3 标记得到了高放射化学产率和纯度。在 SSTR2 转染的 U2OS 细胞中进行 eSOMA-DM1 结合、摄取和内化的体外评估。在携带 H69 肿瘤的小鼠中进行离体生物分布和荧光成像。结果：eSOMA-DM1 对 SSTR2 的 IC50 值与金标准 DOTA-TATE 相似。 U2OS.SSTR2细胞中[111In]In-eSOMA-DM1的摄取比[111In]In-DOTA-TATE低1.2倍。与 [111In]In-DOTA-TATE 相比，H69 异种移植小鼠中 [111In]In-eSOMA-DM1 在所有时间点的肿瘤摄取均​​较高。血液循环时间延长导致[111In]In-eSOMA-DM1在高度血管化的组织（如肺、皮肤和心脏）中积累增加。还观察到通过肾脏、肝脏和脾脏的排泄。结论：eSOMA-DM1 是一种专为 NET 开发的 SMDC，在体外表现出有前景的特性。然而，用[111In]In-eSOMA-DM1获得的体内结果表明需要进行调整以优化其分布。

Background: The main challenges of conventional chemotherapy lie in its lack of selectivity and specificity, leading to significant side effects. Using a small-molecule drug conjugate (SMDC) ensures specific delivery of a cytotoxic drug to the tumor site by coupling it to a targeting vector. This promising strategy can be applied to neuroendocrine tumors (NETs) by choosing a targeting vector that binds specifically to somatostatin receptor subtype 2 (SSTR2). Additionally, incorporation of a bifunctional chelate into the molecule enables complexation of both diagnostic and therapeutic radionuclides. Thus, it facilitates monitoring of the distribution of the SMDC in the body and allows for the implementation of combination therapy. In our study, we designed eSOMA-DM1, a SMDC combining the SSTR2-targeted octreotate peptide and the cytotoxic agent DM1 via a chelate-bridged linker (N3-Py-DOTAGA). This approach warrants conjugation of the targeting vector and the drug at opposite sites to avoid undesired steric hindrance effects. Methods: Synthesis of the DM1 moiety (4) involved a three-step synthetic route, followed by the conjugation to the cyclic peptide, N3-Py-DOTAGA-d-Phe-cyclo[Cys-Tyr-d-Trp-Lys-Thr-Cys]-Thr-OH, through a copper-free click reaction, resulting in eSOMA-DM1. Subsequent labeling with [111In]InCl3 gave a high radiochemical yield and purity. In vitro assessments of eSOMA-DM1 binding, uptake, and internalization were conducted in SSTR2-transfected U2OS cells. Ex vivo biodistribution and fluorescence imaging were performed in H69-tumor bearing mice. Results: eSOMA-DM1 exhibited an IC50 value for SSTR2 similar to the gold standard DOTA-TATE. The uptake of [111In]In-eSOMA-DM1 in U2OS.SSTR2 cells was 1.2-fold lower than that of [111In]In-DOTA-TATE. Tumor uptake in H69-xenografted mice was higher for [111In]In-eSOMA-DM1 at all-time points compared to [111In]In-DOTA-TATE. Prolonged blood circulation led to increased accumulation of [111In]In-eSOMA-DM1 in highly vascularized tissues, such as the lungs, skin, and heart. Excretion through the kidneys, liver, and spleen was also observed. Conclusion: eSOMA-DM1 is a SMDC developed for NET showing promising characteristics in vitro. However, the in vivo results obtained with [111In]In-eSOMA-DM1 suggest the need for adjustments to optimize its distribution.